Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase

Cysteinyl leukotrienes are key mediators in inflammation and have an important role in acute and chronic inflammatory diseases of the cardiovascular and respiratory systems, in particular bronchial asthma. In the biosynthesis of cysteinyl leukotrienes, conversion of arachidonic acid forms the unstable epoxide leukotriene A4 (LTA4). This intermediate is conjugated with glutathione (GSH) to produce leukotriene C4 (LTC4) in a reaction catalysed by LTC4 synthase: this reaction is the key step in cysteinyl leukotriene formation. Here we present the crystal structure of the human LTC4 synthase in its apo and GSH-complexed forms to 2.00 and 2.15 A resolution, respectively. The structure reveals a homotrimer, where each monomer is composed of four transmembrane segments. The structure of the enzyme in complex with substrate reveals that the active site enforces a horseshoe-shaped conformation on GSH, and effectively positions the thiol group for activation by a nearby arginine at the membrane-enzyme interface. In addition, the structure provides a model for how the omega-end of the lipophilic co-substrate is pinned at one end of a hydrophobic cleft, providing a molecular 'ruler' to align the reactive epoxide at the thiol of glutathione. This provides new structural insights into the mechanism of LTC4 formation, and also suggests that the observed binding and activation of GSH might be common for a family of homologous proteins important for inflammatory and detoxification responses.     

An unexpected cooling effect in Saturn's upper atmosphere

The upper atmospheres of the four Solar System giant planets exhibit high temperatures that cannot be explained by the absorption of sunlight. In the case of Saturn the temperatures predicted by models of solar heating are approximately 200 K, compared to temperatures of approximately 400 K observed independently in the polar regions and at 30 degrees latitude. This unexplained 'energy crisis' represents a major gap in our understanding of these planets' atmospheres. An important candidate for the source of the missing energy is the magnetosphere, which injects energy mostly in the polar regions of the planet. This polar energy input is believed to be sufficient to explain the observed temperatures, provided that it is efficiently redistributed globally by winds, a process that is not well understood. Here we show, using a numerical model, that the net effect of the winds driven by the polar energy inputs is not to heat but to cool the low-latitude thermosphere. This surprising result allows us to rule out known polar energy inputs as the solution to the energy crisis at Saturn. There is either an unknown--and large--source of polar energy, or, more probably, some other process heats low latitudes directly.     

Aggregation and vesiculation of membrane proteins by curvature-mediated interactions

Membrane remodelling plays an important role in cellular tasks such as endocytosis, vesiculation and protein sorting, and in the biogenesis of organelles such as the endoplasmic reticulum or the Golgi apparatus. It is well established that the remodelling process is aided by specialized proteins that can sense as well as create membrane curvature, and trigger tubulation when added to synthetic liposomes. Because the energy needed for such large-scale changes in membrane geometry significantly exceeds the binding energy between individual proteins and between protein and membrane, cooperative action is essential. It has recently been suggested that curvature-mediated attractive interactions could aid cooperation and complement the effects of specific binding events on membrane remodelling. But it is difficult to experimentally isolate curvature-mediated interactions from direct attractions between proteins. Moreover, approximate theories predict repulsion between isotropically curving proteins. Here we use coarse-grained membrane simulations to show that curvature-inducing model proteins adsorbed on lipid bilayer membranes can experience attractive interactions that arise purely as a result of membrane curvature. We find that once a minimal local bending is realized, the effect robustly drives protein cluster formation and subsequent transformation into vesicles with radii that correlate with the local curvature imprint. Owing to its universal nature, curvature-mediated attraction can operate even between proteins lacking any specific interactions, such as newly synthesized and still immature membrane proteins in the endoplasmic reticulum.     

Ecology: global warming and amphibian losses

Is global warming contributing to amphibian declines and extinctions by promoting outbreaks of the chytrid fungus Batrachochytrium dendrobatidis? Analysing patterns from the American tropics, Pounds et al. envisage a process in which a single warm year triggers die-offs in a particular area (for instance, 1987 in the case of Monteverde, Costa Rica). However, we show here that populations of two frog species in the Australian tropics experienced increasing developmental instability, which is evidence of stress, at least two years before they showed chytrid-related declines. Because the working model of Pounds et al. is incomplete, their test of the climate-linked epidemic hypothesis could be inconclusive.